Representation of Flexible Biomolecular Shapes

描述（由申请人提供）：分子柔韧性是生物分子的内在特性，通常对其功能至关重要。它的理解对于将结构与生物功能联系起来是重要的，这是计算机辅助药物设计的核心。缺乏分子柔韧性的高水平表征阻碍了当前的模拟方法能够预测复合物呈现药物诱导的受体构象变化。该项目提出了一种基于分层树状结构的分子柔韧性的新型多分辨率编码的发展。这个灵活性树（FT）中的每个节点将表示在给定近似水平上作为刚体移动的原子子集。每个节点都将存储其子节点的运动信息。分配给子节点的形状将用于递归地定义父节点的形状。将开发用于形状和运动卷积的算子，以及用于评估由该树描述的构象的适应度。对接程序AutoDock将扩展到使用FT来表示蛋白质的灵活性。这种数据结构将实现：1)作为不同尺度上嵌套运动的组合的宏观分子灵活性计算模型的高级表示，2)感兴趣的构象子空间的选择性编码，以及3)灵活性对分子形状和性质的影响的研究。该研究为结构分子生物学家定义了一个新的框架，可以使用形状和灵活性信息的统一、多尺度表示来分析分子结构及其相互作用。它将有助于增加我们对生物分子灵活性基本性质的理解，并为在自动对接等计算方法中整合蛋白质灵活性提供基础设施。它还将提供计算工具，以交互式或程序化的方式探索分子在各个细节层面的灵活性。这些工具将通过大量的计算平台提供给科学界，以确保其广泛传播。这些工具有望极大地扩展可以成功模拟的生物系统的范围，从而提高我们发现和优化新药的能力。

DESCRIPTION (provided by applicant): Molecular flexibility is an intrinsic property of bio-molecules and is often essential for their function. Its understanding is important for relating structure to biological function, which is at the heart of computer aided drug design. The lack of high-level representation of molecular flexibility prevents current simulation methods from being able to predict complexes presenting drug-induced conformational changes in the receptor. This project proposes the development of a novel multiresolution encoding of molecular flexibility, based on a hierarchical, tree-like structure. Each node in this Flexibility Tree (FT) will represent a subset of atoms that move as a rigid body at a given level of approximation. Every node will store information about the motion of its children. Shapes assigned to child nodes will be used to define recursively the shape of parent nodes. Operators for the convolution of shape and motion, and for the evaluation of the fitness of conformations described by this tree will be developed. The docking program AutoDock will be extended to represent protein flexibility using the FT. This data structure will enable: 1) the high-level representation in computational models of macro- molecular flexibility as a combination of nested motions occurring at different scales, 2) the selective encoding of a conformational sub-space of interest, and 3) the study of the effects of flexibility on molecular shape and properties. The proposed research defines a novel framework for structural molecular biologists to analyze molecular structures and their interactions using a unified, multi-scale representation of both shape and flexibility information. It will help increase our understanding of the fundamental nature of biomolecular flexibility and provide the infrastructure for integrating protein flexibility in computational methods such as automated docking. It will also provide computational tools to explore, either interactively or programmatically, molecular flexibility at various levels of detail. These tools will be made available to the scientific community on a large number of computational platforms to ensure their wide dissemination. These tools hold the promise of extending dramatically the range of biological systems that can be simulated successfully, and thereby improve our ability to discover and optimize new drugs.